Nav1.4
Description: sodium channel, voltage-gated, type IV, alpha subunit Gene: Scn4a Synonyms: nav1.4, scn4a
SCN4A (also known as HYPP; SkM1; HYKPP; NAC1A; HOKPP2; Nav1.4; Na(V)1.4) encodes Nav1.4, a member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. http://www.ncbi.nlm.nih.gov/gene/6329
Gene
Transcript
Ontology
Accession | Name | Definition | Evidence | |||||||
---|---|---|---|---|---|---|---|---|---|---|
GO:0001518 | voltage-gated sodium channel complex | A sodium channel in a cell membrane whose opening is governed by the membrane potential. | IEA | |||||||
GO:0016021 | integral to membrane | Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. | IEA | |||||||
GO:0016020 | membrane | Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. | IEA |
Calmodulin
CaM (Calmodulin) regulates the current density of NaV1.4. Association with CaM is important for functional expression of NaV1.4. Disrupting the interaction between CaM and the C terminus of NaV1.4 reduced current amplitude by 99%. Calmodulin also was able to modulate the inactivation kinetics of Nav1.6, but not Nav1.4, currents in a calcium-dependent manner. [53].
(Calmodulin, a 16.7 kDa protein that is expressed in virtually all eukaryotic cells, can induce changes in target proteins via its binding per se and in response to changes in calcium concentration [823]. For example, the activity of sodium channels in Paramecium tetraurelia is CaM-dependent [824], and CaM plays a crucial role in the modulation of calcium channels [825].)
Ranolazine
Ranolazine is an antianginal and anti-ischemic drug that is used in patients with chronic angina [833]. Ranzoline blocks Na+ currents of Nav1.4. Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. At its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na+ channels. Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate. [827]
Tetrodotoxin
Nav1.4 is tetrodotoxin sensitive (non selective). [834]
Protein
The skeletal muscle a subunit functions as ion-conducting channel and consists of large polypeptides (1700–2000 amino acids) that fold into four highly homologous somains (repeats I-IV) containing six transmembrane segments each (S1-S6). The S6 transmembrane segments and the S5- S6 loops form the ion selective pore, and the S4 segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected by intracellular loops; one of them, the III-IV linker, contains the supposed inactivation particle of the channel. When inserted in the membrane, the four repeats of the protein fold to generate a central pore. [1403],[815]
Amino acid Ile-1575 in the middle of transmembrane segment 6 of domain IV (DIV-S6) in the adult rat skeletal muscle isoform of the voltage-gated sodium channel (rNaV1.4) may act as molecular switch allowing for interaction between outer and inner vestibules. [829]
Nav1.4 channels are located in the sarcolemma and T-tubular membranes, with a high density near the endplate of the muscle cell. [1406]
Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain or heart[834].
Relative mRNA expression levels of Nav1.4, analyzed by RT-PCR, were significantly higher in ovarian cancers cells compared with normal ovarian tissues and relative mRNA expression levels Nav1.4 were significantly increased in highly metastatic ovarian cancer cells (Caov-3 and SKOV-3) compared with low-metastatic ovarian cancer cells (Anglne). [830]
NaV1.4 is responsible for the generation and propagation of action potentials that initiate muscle contraction.
Channelopathies
Mutations in NaV1.4 channels increase channel activity by impairing fast and/or slow inactivation causing hereditary sodium channelopathies of skeletal muscle such as [[1390]:
* Hyperkalaemic periodic paralysis
* Hypokalaemic periodic paralysis
* Paramyotonia congenital
* Potassium-aggravated myotonia
* Congenital myasthenic syndrome
* Muscle stiffness [826]
VSGC blockers such as mexiletine, flecainide and other lidocaine analogues can reduce repetitive firing of action potential because of their use-depended properties, a mechanism that leads to a preferential action on channels with pathogenic gain-of-function mutations. These blockers reduce muscle stiffness in potassium-aggravated myotonia and paramyotonia congenita by promoting the inactivated state of NaV1.4 by inducing a hyperpolarized shift in steady-state inactivation and by prolonging recovery time from inactivation. Symptoms of muscle weakness are often caused by other pathogenic factors and cannot be treated sufficiently with VGSC blockers [[1390].
Expression of skeletal muscle sodium channel (Nav1.4) prevents reperfusion arrhythmias in murine heart. [[828]
In addition to fast and slow inactivation there is a third type of inactivation named ultra-slow inactivation. This process was described inNav1.4 when the alanine in position 1529 (A1529) is replaced by aspartate (D) in the domain IVP-loop. Binding of the fast inactivating particle inhibits this process. This result demonstrates that there are interactions (mostly, allosteric modulation) among the different inactivation events. [1376], [1405]
Model
References
Herzog RI
et al.
Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties.
J. Neurosci.,
2003
Sep
10
, 23 (8261-70).
Chin D
et al.
Calmodulin: a prototypical calcium sensor.
Trends Cell Biol.,
2000
Aug
, 10 (322-8).
Saimi Y
et al.
Paramecium Na+ channels activated by Ca(2+)-calmodulin: calmodulin is the Ca2+ sensor in the channel gating mechanism.
J. Membr. Biol.,
1995
Apr
, 144 (257-65).
Zühlke RD
et al.
Calmodulin supports both inactivation and facilitation of L-type calcium channels.
Nature,
1999
May
13
, 399 (159-62).
Kasama S
et al.
[A case of muscle sodium channelopathy with markedly high value of serum creatine kinase and mild eyelid myotonia].
Rinsho Shinkeigaku,
2011
Feb
, 51 (120-4).
Wang GK
et al.
State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.
Mol. Pharmacol.,
2008
Mar
, 73 (940-8).
Anyukhovsky EP
et al.
Expression of skeletal muscle sodium channel (Nav1.4) or connexin32 prevents reperfusion arrhythmias in murine heart.
Cardiovasc. Res.,
2011
Jan
1
, 89 (41-50).
Zarrabi T
et al.
A molecular switch between the outer and the inner vestibules of the voltage-gated Na+ channel.
,
2010
Oct
6
, ().
Gao R
et al.
Expression of voltage-gated sodium channel alpha subunit in human ovarian cancer.
Oncol. Rep.,
2010
May
, 23 (1293-9).
831
Sokolov S
et al.
Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations.
J. Gen. Physiol.,
2010
Aug
, 136 (225-36).
832
Ferrera L
et al.
Beta1-subunit modulates the Nav1.4 sodium channel by changing the surface charge.
,
2006
Jun
, 172 (139-50).
Pepine CJ
et al.
A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group.
Am. J. Cardiol.,
1999
Jul
1
, 84 (46-50).
Goldin AL
Resurgence of sodium channel research.
Annu. Rev. Physiol.,
2001
, 63 (871-94).
Catterall WA
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.
Neuron,
2000
Apr
, 26 (13-25).
852
Bennett ES
et al.
Voltage-gated Na+ channels confer invasive properties on human prostate cancer cells.
Pflugers Arch.,
2004
Mar
, 447 (908-14).
857
Kondratiev A
et al.
Altered gating and local anesthetic block mediated by residues in the I-S6 and II-S6 transmembrane segments of voltage-dependent Na+ channels.
Mol. Pharmacol.,
2003
Sep
, 64 (741-52).
Jurkat-Rott K
et al.
Paroxysmal muscle weakness: the familial periodic paralyses.
J. Neurol.,
2006
Nov
, 253 (1391-8).
1404
Biswas S
et al.
Calmodulin regulation of Nav1.4 current: role of binding to the carboxyl terminus.
J. Gen. Physiol.,
2008
Mar
, 131 (197-209).
Goldin AL
Mechanisms of sodium channel inactivation.
Curr. Opin. Neurobiol.,
2003
Jun
, 13 (284-90).
Zhao J
et al.
Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold-induced myotonia in French Canadians.
J. Physiol. (Lond.),
2012
Jun
1
, 590 (2629-44).
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